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首页> 外文学位 >Regulator of G protein signaling 6 (RGS6), a multifarious and pleiotropic modulator of G protein coupled receptor signaling in brain.
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Regulator of G protein signaling 6 (RGS6), a multifarious and pleiotropic modulator of G protein coupled receptor signaling in brain.

机译：G蛋白信号传导调节剂6（RGS6），大脑中G蛋白偶联受体信号传导的多种多样的调节剂。

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摘要

Transmembrane signal transduction by ligand-activated G protein-coupled receptors (GPCRs) controls virtually every aspect of mammalian physiology, and this receptor class is the target of 40-50% of currently marketed pharmaceuticals. In addition to the clinical use of direct GPCR agonists and antagonists, it is now believed that GPCR effectors and regulators may also be viable drug targets with improved therapeutic efficacy and specificity. The prototypic role of Regulator of G protein Signaling (RGS) proteins is inhibition of G protein signaling through acceleration of GTP hydrolysis by Galpha, which promotes re-association of Galpha and Gbetagamma subunits with the receptor at the cell membrane. In this way, RGS proteins determine the magnitude and duration of the cellular response to GPCR stimulation. Though RGS protein biochemistry has been well elucidated in vitro, the physiological functions of each RGS family member remain largely unexplored.;RGS6 belongs to the R7 subfamily of RGS proteins originally identified in brain. Our acquisition of an RGS6-/- mouse allowed us to survey RGS6 expression in all tissues of the body revealing the greatest expression of RGS6 in brain. Despite robust neural RGS6 expression, little is known regarding functional roles of RGS6 in the brain and spinal cord. In addition, we identified several novel, higher molecular weight RGS6 immunoreactive bands specifically present in the nervous system. The plan of this thesis work was multifaceted. We sought to elucidate novel GPCR signaling cascades modulated by RGS6 in brain while simultaneously characterizing the expression patterns and identity of the novel RGS6 species specifically detected in the nervous system. Considering the large diversity of RGS6 isoforms present in brain, the abundance of potential RGS6 binding partners, and the possibility of discovering new mechanisms involved in RGS6 regulation, elucidation of the novel RGS6 molecular species is of paramount importance.;Utilizing RGS6-/- mice we identified RGS6 as a critical modulator of two GPCRs in brain. First, by inhibiting the serotonin receptor 1A (5-HT1AR)-adenylyl cyclase (AC) axis, RGS6 functions to promote anxiety- and depression-related behaviors in mice. As a result, RGS6 -/- mice exhibit a robust anxiolytic and antidepressant phenotype remarkably similar to that of animals treated chronically with therapeutic doses of selective serotonin reuptake inhibitors (SSRIs). RGS6 also inhibits GABAB receptor (GABABR)-G protein- activated inwardly rectifying potassium (GIRK) channel current in cerebellar granule cells, and loss of RGS6 results in cerebellar ataxia and gait abnormalities reversible by GABABR blockade. Furthermore, evaluation of voluntary alcohol drinking behaviors in WT versus RGS6-/- mice revealed a striking reduction in alcohol intake resulting from RGS6 loss in both acute and chronic alcohol consumption paradigms due, at least in part, to potentiation of GABA BR signaling. Thus, RGS6 inhibitors have potential clinical utility in the treatment of mood disorders and alcoholism.;We have shown that one novel RGS6 immunoreactive band expressed in the brain and spinal cord is a phospho-protein sensitive to lambda phosphatase-mediated dephosphorylation. Further, new information acquired from PCR amplification of RGS6 mRNA species from human brain cDNA libraries has necessitated substantial revisions to the RGS6 splicing scheme devised by the Fisher laboratory in 2003. To the 36 isoforms generated from two alternate transcription start sites (RGS6L vs. RGS6), the inclusion or exclusion of exons 14 and 17, and variable splicing to one of 7 different 3' terminal exons, we have added the possible insertion of three novel internal exons (A1, A2, A3), a retained intron, and two new 3' terminal exons. As a result, the number of RGS6 mRNAs present in brain could be as many as 248 unique species, an astonishing diversity unprecedented in the RGS protein family.
机译：配体激活的G蛋白偶联受体（GPCR）的跨膜信号转导实际上控制着哺乳动物生理学的各个方面，并且该受体类别是目前市场上40％至50％药物的目标。除了直接使用GPCR激动剂和拮抗剂的临床用途外，现在认为GPCR效应子和调节剂也可能是具有改善的治疗功效和特异性的可行药物靶标。 G蛋白信号调节剂（RGS）的调节剂的原型作用是通过Galpha加速GTP水解来抑制G蛋白信号传导，从而促进Galpha和Gbetagamma亚基与细胞膜受体的重新结合。以这种方式，RGS蛋白确定了细胞对GPCR刺激的反应的幅度和持续时间。尽管已经很好地阐明了RGS蛋白的生物化学作用，但每个RGS家族成员的生理功能仍未得到充分探索。RGS6属于最初在大脑中鉴定出的RGS蛋白的R7亚家族。我们获得的RGS6-/-小鼠使我们能够调查人体所有组织中RGS6的表达​​，从而揭示RGS6在脑中的最大表达。尽管神经RGS6表达强健，但关于RGS6在脑和脊髓中的功能作用知之甚少。此外，我们鉴定了神经系统中特有的几种新型，更高分子量的RGS6免疫反应带。论文工作的计划是多方面的。我们试图阐明由RGS6在大脑中调节的新型GPCR信号级联，同时表征在神经系统中特异性检测到的新型RGS6种类的表达模式和特性。考虑到大脑中存在的RGS6同工型的多样性，潜在的RGS6结合伴侣的丰富性以及发现与RGS6调控有关的新机制的可能性，阐明新型RGS6分子种类至关重要。;利用RGS6-/-小鼠我们确定RGS6是大脑中两个GPCR的关键调节剂。首先，RGS6通过抑制5-羟色胺受体1A（5-HT1AR）-腺苷酸环化酶（AC）轴，起到促进小鼠焦虑和抑郁相关行为的作用。结果，RGS6-/-小鼠表现出强大的抗焦虑和抗抑郁表型，与用治疗剂量的选择性5-羟色胺再摄取抑制剂（SSRIs）长期治疗的动物相似。 RGS6还抑制小脑颗粒细胞中GABAB受体（GABABR）-G蛋白激活的内向整流钾（GIRK）通道电流，RGS6的丢失导致小脑共济失调和步态异常，可通过GABABR阻断来逆转。此外，对WT和RGS6-/-小鼠的自愿饮酒行为的评估显示，急性和慢性饮酒范例中RGS6的损失至少部分归因于GABA BR信号增强，导致酒精摄入量显着减少。因此，RGS6抑制剂在治疗情绪障碍和酒精中毒方面具有潜在的临床应用价值。我们已经证明，在大脑和脊髓中表达的一种新型RGS6免疫反应带是对λ磷酸酶介导的去磷酸化敏感的磷酸化蛋白。此外，从人脑cDNA文库中RGS6 mRNA的PCR扩增中获得的新信息需要对Fisher实验室在2003年设计的RGS6剪接方案进行实质性修订。从两个替代转录起始位点（RGS6L与RGS6）生成的36个亚型），包含或排除第14和17号外显子，以及可变剪接至7个不同的3'末端外显子之一，我们增加了可能插入的三个新内部内显子（A1，A2，A3），一个保留的内含子和两个新的3'末端外显子。结果，大脑中存在的RGS6 mRNA的数量可能多达248种，这是RGS蛋白家族中前所未有的惊人多样性。

著录项

  • 作者

    Stewart, Adele Marie.;

  • 作者单位

    The University of Iowa.;

  • 授予单位 The University of Iowa.;
  • 学科 Health Sciences Pharmacology.;Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 211 p.
  • 总页数 211
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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